Cell adhesion receptors play a critical role in tumor progression and metastasis. While in normal epithelial tissues cells are tightly adhere, cells in high-grade tumors are only loosely attached to each other, with cells at the tumor periphery displaying prominent loss of cell-cell adhesion and local tissue invasion. Decreased intercellular adhesion in high-grade tumors is often caused by a decreased expression or a complete loss of important cell-cell adhesion proteins. E-cadherin is clearly the best-studied example of such a protein and we have extensive knowledge concerning the mechanisms and the role of E-cadherin in tumor progression and metastasis. Our laboratory has being focused on understanding the role and significance of alpha-catenin, a cell-cell adhesion protein that links cadherin and catenins at the cell membrane with the actin cytoskeleton. Alpha-catenin is often lost or down regulated in high-grade epithelial tumors and loss of alpha-catenin correlates with metastatic progression and poor patient prognosis. We have recently demonstrated that alpha-catenin has an important tumor-suppressor function in Squamous Cell Carcinoma. The analysis of potential molecular mechanisms revealed a prominent connection between alpha-catenin and the Hippo signal transduction pathway. We present preliminary evidence demonstrating an important role of alpha-catenin in regulation of normal homeostasis of epidermal stem cells. We also show that the principal signaling function of alpha-catenin involves regulation of the activit of Src-family tyrosine kinases. In this grant application we propose to investigate the role of alpha-catenin in formation of cancer initiating cells in Squamous Cell Carcinoma and analyze the mechanisms and significance of Src-family kinases in regulation of Hippo signal transduction pathway, tumor initiation and progression.